Bimodal Modulation of Ipsilateral Spinal-Coeruleo-Spinal Pathway in CRPS: A Novel Model for Explaining Different Clinical Features of the Syndrome

Abstract

Objective: The objective is to present a hypothesis to explain the sensory, autonomic, and motor disturbances associated with complex regional pain syndrome (CRPS) syndrome. Methods: The author reviewed the available and relevant literature, which was supplemented with research on experimental animal models, with a focus on how they may translate into humans, particularly in areas about pathophysiologic mechanisms of CRPS. Results: We propose that different CRPS subtypes may result from facilitative or inhibitory influences exerted by the spinal-coeruleo-spinal pathway in three sites at the spinal cord: the dorsal horn (DH), intermediolateral cell column (IML) and ventral horn (VH). A facilitatory influence over DH may have a pronociceptive effect that explains exacerbated pain, sensory disturbances, and spreading sensitization and neuroinflammation. Conversely, a facilitatory influence over preganglionic neurons located in IML cell column may increase sympathetic outflow with peripheral vasoconstriction, which leads to cold skin, ipsilateral limb ischaemia, and sympathetically maintained pain (SMP). For patients presenting with these symptoms, a descending inhibitory influence would be predicted to result in decreased sympathetic outflow and warm skin, as well as impairment of peripheral vasoconstrictor reflexes. Finally, a descending inhibitory influence over VH could explain muscle weakness and decreased active range of motion, while also facilitating motor reflexes, tremor and dystonia. Conclusions: The proposed model provides a mechanistically based diagnostic scheme for classifying and explaining the sensory, autonomic and motor disturbances associated with CRPS syndrome.